Complement is part of the innate immune system that plays an important role in host defense. Recent evidence suggests that complement may also play an adjuvant role in T cell immunity. While important in host defense, activated complement is a double-edged sword that, if not properly regulated, can cause severe inflammatory tissue injury. To protect the host from complement attack, several membrane-anchored and fluid-phase complement regulatory proteins have evolved. Decay-accelerating factor (DAF) and factor H (fH) are two prototypical complement regulators, one residing on the cell surface (DAF) and the other existing in the plasma (fH). Dysfunction of DAF and fH, as well as other complement regulators, are associated with several human inflammatory disorders. The pathogenesis of these diseases, the relative activity and tissue specificity of complement regulators, and the mechanism by which DAF and complement effectors regulate T cell immunity are outstanding questions that remain to be addressed. In the present proposal, we will use several knockout and transgenic mouse models to address these questions and to test the following two hypotheses: that tissue sensitivity to complement attack is determined by combined activities of membrane and fluid phase complement regulators;and that DAF and complement regulate T cell immunity through a mechanism that is independent of an intrinsic role of DAF on T cells. We propose the following three specific aims: 1): To characterize the relative roles of DAF, Crry and fH in vivo in host cell protection;2): To determine the site and mechanism of action of DAF in regulating T cell immunity;3) To determine the role, site and mechanism of action of C5aR and C3aR signaling in T cell immunity. These studies will provide novel insights into the mechanism of action of complement and its regulators in innate and adaptive immunity and inflammation, and will facilitate the understanding and treatment of human autoimmune and inflammatory disorders associated with complement dysregulation. PUBLIC HEALTH RELEVANCE: This project studies the role of the complement system in tissue injury and host immune response. We will use gene ablated and transgenic mice to create animal models wherein complement is abnormally activated to mimic several human inflammatory diseases. We will also perform experiments to understand how complement might help the host develop a robust T cell immune response for fighting infection. These studies will increase our understanding of the pathogenesis of human inflammatory diseases and may ultimately lead to the development of new therapeutic drugs for autoimmune and inflammatory conditions.